The question of the origins of baseball has been the subject of debate and controversy for more than a century. Baseball and the other modern bat, ball, and running games – stoolball, cricket and rounders – were developed from folk games in early Britain, Ireland, and Continental Europe (such as France and Germany). Early forms of baseball had a number of names, including "base ball", "goal ball", "round ball", "fetch-catch", "stool ball", and, simply, "base". In at least one version of the game, teams pitched to themselves, runners went around the bases in the opposite direction of today's game, much like in the Nordic brännboll, and players could be put out by being hit with the ball. Just as now, in some versions a batter was called out after three strikes.

Although much is unclear, as one would expect of children's games of long ago, this much is known: by the mid-18th century a game had appeared in the south of England which involved striking a pitched ball and then running a circuit of bases. Rounders is referenced in 1744 in the children's book A Little Pretty Pocket-Book where it was called Base-Ball. English colonists took this game to North America with their other pastimes, and in the early 1800s variants were being played on both sides of the ocean under many appellations.  However, the game was very significantly altered by amateur men's ball clubs in and around New York City in the middle of the 19th century, and it was this heavily revised sport that became modern baseball.

Folk games in early Britain, Ireland and continental Europe

A number of folk games in early Britain and continental Europe had characteristics that can be seen in modern baseball (as well as in cricket and rounders). Many of these early games involved a ball that was thrown at a target while an opposing player defended the target by attempting to hit the ball away. If the batter successfully hit the ball, he could attempt to score points by running between bases while fielders would attempt to catch or retrieve the ball and put the runner out.
Folk games differed over time, place, and culture, resulting in similar yet variant forms. These  games had no standard documented rules and instead were played according to historical customs. These games tended to be played by working classes, peasants, and children. Early folk games were often associated with earlier religious ceremonies and worship rituals. These games became discouraged and even altogether prohibited by subsequent governing states and religious authorities.

Aside from obvious differences in terminology, the games differed in the equipment used (ball, bat, club, target, etc., which were usually just whatever was available), the way in which the ball was thrown, the method of scoring, the method of making outs, the layout of the field and the number of players involved. Very broadly speaking, these games can be roughly divided into forms of longball, where the batter ran out to a single point or line and back, as in cricket, and roundball, where there was a circuit of multiple bases. There were also games (e.g. stool-ball, trap-ball) which involved no running at all.

Oină

Oină is a Romanian traditional sport, a form of longball similar in many ways to lapta.

The name "oină" was originally "hoina", and is derived from the Cuman word oyn "game" (a cognate of Turkish oyun).
The oldest direct mention comes from 1364.

In 1899, Spiru Haret, the minister of education decided that oină was to be played in schools in physical education classes.  He organized the first annual oină competitions.

The Romanian Oină Federation ("Federaţia Română de Oină") was founded in 1932, and was reactivated at the beginning of the 1950s, after a brief period when it was dissolved.

Today, there are two oină federations: one in Bucharest, Romania and another one in Chişinău, Moldova.

Stoolball
In an 1802 book entitled The Sports and Pastimes of the People of England, Joseph Strutt claimed to have shown that baseball-like games can be traced back to the 14th century, in particular an English game called stoolball. The earliest known reference to stoolball is in a 1330 poem by William Pagula, who recommended to priests that the game be forbidden within churchyards.

In stoolball, one player throws the ball at a target while another player defends the target. Originally, the target was defended with a bare hand. Later, a bat of some kind was used (in modern stoolball, a bat like a very heavy table tennis paddle is used). "Stob-ball" and "stow-ball" were regional games similar to stoolball.  What the target originally was in stoolball is not certain; it was possibly a tree stump, since "stob" and "stow" all mean stump in some local dialects. ("Stow" could also refer to a type of frame used in mining). It is notable that in cricket to this day, the uprights of the wicket are called "stumps". Of course, the target could well have been whatever was convenient, perhaps even a gravestone (hence Pagula's objection to churchyard play). A 17th-century book on games specifies a stool.

According to one legend, milkmaids played stoolball while waiting for their husbands to return from the fields. Another theory is that stoolball developed as a game played after attending church services, in which case the target was probably a church stool. An 18th-century poem depicts men and women playing together (the women using their aprons to catch batted balls), and it and other references associate the game especially with the Easter season.

There were several versions of stoolball. In the earliest versions, the object was primarily to defend the stool. Successfully defending the stool counted for one point, and the batter was out if the ball hit the stool. There was no running involved. Another version of stoolball involved running between two stools, and scoring was similar to the scoring in cricket. In perhaps yet another version there were several stools, and points were scored by running around them as in baseball.

When Englishmen came to America, they brought stoolball with them. William Bradford in his diary for Christmas Day, 1621, noted (with disapproval) how the men of Plymouth were "frolicking in þe street, at play openly; some pitching þe barre, some at stoole-ball and shuch-like sport". Because of the different versions of stoolball, and because it was played not only in England, but also in colonial America, stoolball is considered by many to have been the common ancestor of cricket, baseball and rounders.

Dog and cat
Another early folk game was "dog and cat" (or "cat and dog"), which probably originated in Scotland. In cat and dog an oblong piece of wood called a cat is thrown at a hole in the ground while another player defends the hole with a stick (a dog). In some cases there were two holes and, after hitting the cat, the batter would run between them while fielders would try to get the runner out by putting the cat in the hole before the runner got to it. Dog and cat thus resembled cricket.

Horne-billets
This game, otherwise unknown, was described in Francis Willughby's Book of Games (ca. 1670), which included rules for over 130 pastimes including stool-ball and stow-ball. It is significant in that it involved both a bat and base-running, although it was played with a wooden cat rather than a ball and the multiple "bases" were holes in the ground: the batter reached safety by putting the end of his bat in a hole before the fielders could put the cat in it. This has echoes in cricket's manner of scoring runs by touching the bat to the ground across the crease before the fielders can hit the nearby wicket with the ball.

Trap ball
In trap ball, played in England since the 14th century, a ball was thrown in the air, to be hit by a batsman and fielded. In some variants a member of the fielding team threw the ball in the air; in some, the batter tossed it himself as in fungo; in others, the batsman caused the ball to be tossed in the air by a simple lever mechanism: versions of this, called bat and trap and Knurr and spell, are still played in some English pubs. In trap-ball there was no running, instead the fielders attempted to throw the ball back to within a certain distance of the batter's station. Trap-ball may be the origin of the concept of foul lines; in most variants the ball had to be hit between two posts to count.

A related game was tip-cat; in this, the "cat" was an oblong piece of wood (as in dog-and-cat); it tapered toward each end, rather like a rugby ball or American football, so that striking one end would flip it into the air much like the trap in trap-ball so that it could be struck with a stick or bat.

Base
An old English game called "base" or "prisoners' base", described by George Ewing at Valley Forge, was apparently not much like baseball. There was no bat and no ball involved. The game was more like a fancy game of team "tag", although it did share the concept of places of safety, bases, with baseball.

Cricket
The history of cricket prior to 1650 is something of a mystery. Games believed to have been similar to cricket had developed by the 13th century. There was a game called "creag", and another game, "Handyn and Handoute" (Hands In and Hands Out), which was made illegal in 1477 by King Edward IV, who considered the game childish, and a distraction from compulsory archery practice.

References to a game actually called "cricket" appeared around 1550. It is believed that the word cricket is based either on the word cric, meaning a crooked stick (cognate with English crook): early forms of cricket used a curved bat somewhat like a hockey stick; or on a Middle Dutch phrase for hockey, met de (krik ket)sen ("with the stick chase"), or on the Flemish word "krickstoel", which refers to a stool upon which one kneels in church and which the early long, low wicket resembled. The word is etymologically related to French croquet- early forms of which were also played with a curved stick rather than a mallet.

The earliest known mention of baseball, as a children's game, dates from the same year (1744) in which the Artillery Ground Laws formalised the rules of what was already a first-class, professional sport sponsored by nobility and upon which vast wagers were laid.

English colonists played cricket along with their other games from home, and it is mentioned many times in 18th-century American sources. As an organized sport, the Toronto Cricket Club was established in that city by 1827 and the St George's Cricket Club was formed in 1838 in New York City (membership restricted to British-born men). Teams from the two clubs faced off in the first international cricket game in 1844 which Toronto won by 23 runs. Many of the early New York club baseball players were also cricketers, and the earliest recorded inter-club baseball game was played on the Union Star Cricket Grounds in Brooklyn.

Rounders

The British game most similar to baseball, and most mentioned as its ancestor or nearest relation, is rounders. Like baseball, the object is to strike a pitched ball with a bat and then run a circuit of four bases to score. The batter must strike at a good ball and run in an anti-clockwise direction around the first, second, and third base and home to the fourth, though they may stay at any of the first three. A batter is out if the ball is caught; if the base to which they are running to is touched with the ball; or if, while running, they are touched with the ball by a fielder. Nine players constitute a team, with the fielding side consisting of the bowler, the backstop (catcher), a player on each of the four bases, and three deep fielders. Popular among British and Irish school children, and especially among girls, as of 2015 rounders is played by seven million children in the UK.

In 1828, William Clarke in London published the second edition of The Boy's Own Book, which included the rules of rounders (in fact the earliest known use of that name), and the first printed description in English of a bat and ball base-running game played on a diamond. The following year, the book was published in Boston, Massachusetts. The exact same rules were reprinted verbatim in Robin Carver's The Book of Sports (Boston, 1834), except they were headed not "Rounders" but "Base, or Goal-ball."

British baseball

A unique British sport, known as British baseball, is still played in parts of Wales and England. Although confined mainly to the cities of Cardiff, Newport and Liverpool, the sport boasts an annual international game between representative teams from the two countries. British "baseball", however, is much more akin to rounders, as it was in fact called until 1892, and represents a rounders variant somewhat hybridized under the influence of 19th-century American touring teams; it is in fact the last survival in Great Britain of the once-widespread adult club rounders.

Early mentions of baseball
According to many sources, the earliest appearance of the word "baseball" dates from 1700, when Anglican bishop Thomas Wilson expressed his disapproval of "Morris-dancing, cudgel-playing, baseball and cricket" occurring on Sundays. However, David Block, in Baseball Before We Knew It (2005), reports that the original source has "stoolball" for "baseball". Block also reports the reference appears to date to 1672, rather than 1700.

A 1744 book in England by children's publisher John Newbery called A Little Pretty Pocket-Book includes a woodcut of a game similar to three-base stoolball or rounders and a rhyme entitled "Base-Ball". This is the first known instance of the word baseball in print.

In 1755, a book entitled The Card by John Kidgell, in volume 1 on page 9, mentions baseball: "the younger Part of the Family, perceiving Papa not inclined to enlarge upon the matter, retired to an interrupted Party at Base-Ball (an infant Game, which as it advances in its teens, improved into Fives)." Although A Little Pretty Pocket-Book first appeared eleven years earlier, no copies of the first or other early editions have surfaced to date, only the tenth and later editions from 1760 forward. Therefore, The Card was the oldest surviving reference to baseball until the Bray diary was discovered in 2008.

The earliest recorded game of base-ball involved none other than the family of the Prince of Wales, played indoors in London in November 1748. The Prince is reported as playing "Bass-Ball" again in September 1749 in Walton-on-Thames, Surrey, against Lord Middlesex. The English lawyer William Bray wrote in his diary that he had played a game of baseball on Easter Monday 1755 in Guildford, also in Surrey.
 The word "baseball" first appeared in a dictionary in 1768, in A General Dictionary of the English Language compiled by the editors of the Encyclopædia Britannica (first published the same year), with the unhelpful definition "A rural game in which the person striking the ball must run to his base or goal."

By 1796, the rules of this English game were well enough established to earn a mention in the German Johann Christoph Friedrich GutsMuths' book on popular pastimes. In it he described "" ('Ball with safe places, or the English base-ball') as a contest between two teams in which "the batter has three attempts to hit the ball while at the home plate"; only one out was required to retire a side. Gutsmuth included a diagram of the field which was very similar to that of town ball. Notably, Gutsmuths is the earliest author to explicitly mention the use of a bat, although in this case it was a flat wooden paddle about 18 inches long, swung one-handed.

The French book  is the second known book to contain printed rules of a batting/base/running game. It was printed in Paris in 1810 and lays out the rules for  ("poisoned ball"), in which there were two teams of eight to ten players, four bases (one called home), a pitcher, a batter, "soaking" and flyball outs; however, the ball apparently was struck by the hand.

Another early print reference is Jane Austen's novel Northanger Abbey, originally written 1798–1799. In the first chapter the young English heroine Catherine Morland is described as preferring "cricket, base ball, riding on horseback and running about the country to books". About the same time, Austen's cousin Cassandra Cooke mentioned baseball in her novel Battleridge.

In her 1820s "Village Sketch" Jack Hatch, author Mary Russell Mitford wrote:

In 1828, William Clarke of London published the second edition of The Boy's Own Book, which included the earliest known mention of a game called "rounders," and contains under that heading the first printed description in English of a bat and ball base-running game played on a diamond. The following year, the book was published in Boston, Massachusetts. Similar rules were published in Boston in The Book of Sports, written by Robin Carver in 1834, except Carver called the game "Base or Goal ball". Clarke's "rounders" description would be reprinted many times on both sides of the Atlantic in ensuing decades, under various names.

Early baseball in America
Charting the evolution of the game that became modern baseball is difficult before 1845. The Knickerbocker Rules describe a game that had been played for some time, but for how long is uncertain. Shane Foster was the first to come up with suspicions about the origins.

There were once two camps. One, mostly English, asserted that baseball evolved from a game of English origin (probably rounders); the other, almost entirely American, said that baseball was an American invention (perhaps derived from the game of one-ol'-cat). Apparently they saw their positions as mutually exclusive. Some of their points seem more national loyalty than evidence: Americans tended to reject any suggestion that baseball evolved from an English game, while some English observers concluded that baseball was little more than their rounders without the round. One English author went so far as to declare that the Knickerbocker Club comprised English expatriates who introduced "their" game to America for the first time in 1845. The Mills Commission, at the other extreme, created an "official" and entirely fictional All-American version attributing the game's invention to Abner Doubleday in 1839 at Cooperstown, New York (current site of the National Baseball Hall of Fame and Museum).

Both were entirely wrong, since this much is clear: baseball, or a game called "base ball", had been played in America for many years by then. The earliest explicit reference to the game in America is from March 1786 in the diary of a student at Princeton, John Rhea Smith: "A fine day, play baste ball in the campus but am beaten for I miss both catching and striking the ball." There is a possible reference a generation older, from Harvard; describing the campus buttery in the 1760s, Sidney Willard wrote "Besides eatables, everything necessary for a student was there sold, and articles used in the playgrounds, such as bats, balls etc. ... Here it was that we wrestled and ran, played at quoits and cricket, and various games of bat and ball."

A 1791 bylaw in Pittsfield, Massachusetts banned the playing of "any game of wicket, cricket, baseball, batball, football, cats, fives, or any other game played with ball" within 80 yards of the town meeting house to prevent damage to its windows. Worcester, Massachusetts outlawed playing baseball "in the streets" in 1816.

There are other mentions of baseball during the early 19th century.  An advertisement for Kensington House in the New York Evening Post dated June 6, 1821, said "The grounds of Kensington House are spacious, and well adapted to the playing the noble game of cricket, base, trap-ball, quoits and other amusements, and all the apparatus necessary for the above games will be furnished to clubs and parties."

The April 25, 1823 edition of the (New York) National Advocate included this:

Two years later the following notice appeared in the July 13, 1825 edition of the Delhi (New York) Gazette: "The undersigned, all residents of the new town of Hamden, with the exception of Asa Howland, who has recently removed into Delhi, challenge an equal number of persons of any town in the County of Delaware, to meet them at any time at the house of Edward B. Chace, in said town, to play the game of Bass-Ball, for the sum of one dollar each per game."

Thurlow Weed in his memoir recalled organized club baseball in Rochester, New York in 1825:

The first recorded game of baseball under the later codified rules was played in New York on September 23, 1845, between the New York Baseball Club and the Knickerbocker Baseball Club. American baseball was allegedly played in Beachville, Ontario in 1838. However, there is no consensus as to the rules that were used or whether it can be considered the first "baseball" game. A firsthand account and the rules of the game were recalled by Dr. Adam E. Ford, who had witnessed the game as a six-year-old boy, in an 1886 issue of The Sporting Life magazine in Denver, Colorado; he described the game in remarkable detail, including the precise distances between the irregular bases and how the ball was constructed. However, some historians, such as David Block, have expressed doubts as to the veracity and rather incredible specificity of Ford's memory, and indeed compared it to Abner Graves' very similar yarn about Abner Doubleday.

In that letter, Ford refers to 'old grayhairs' at the time, who had played this game as children, suggesting that the origins of baseball in Canada go back into the 18th century. Very similar instances were recorded by John Montgomery Ward in his 1888 book Base-Ball: How to Become a Player, with the Origins, History and Explanation of the Game, in which he recounts several elderly men recalling having played as boys, covering a span from the 1790s to the 1830s; among others, Oliver Wendell Holmes, Sr. recalled playing at Harvard, from which he graduated in 1829.

Cricket and rounders
That baseball is based on older English games such as stool-ball, trap-ball and tip-cat with possible influences from cricket is difficult to dispute. On the other hand, baseball as played in the New World has many elements that are uniquely American. The earliest published author to muse on the origin of baseball, John Montgomery Ward, was suspicious of the often-parroted claim that rounders is the direct ancestor of baseball, as both were formalized in the same time period. He concluded, with some amount of patriotism, that baseball evolved separately from town-ball (i.e. rounders), out of children's "safe haven" ball games.

Games played with bat-and-ball together may all be distant cousins; the same goes for base-and-ball games. Bat, base, and ball games for two teams that alternate in and out, such as baseball, cricket, and rounders, are likely to be close cousins. They all involve throwing a ball to a batsman who attempts to "bat" it away and run safely to a base, while the opponent tries to put the batter-runner out when liable ("liable [to be put out]" is the baseball term for unsafe). Certainly, baseball is related to cricket and rounders, but exactly how, or how closely, has not been established. The only certain thing is that cricket is much older than  baseball, and that cricket was very popular in colonial America and the early United States, fading only with the explosive popularity of New York baseball after the Civil War. Baseball owes to cricket some adopted terminology, such as "outs", "innings", "runs" and "umpires". There was also, "wicket", a countrified form of cricket once very popular in New England, which retained the old-fashioned wide, low two-stump wicket, and in which the large ball was rolled along the ground.

The likelihood is that "base ball" and "rounders" (along with "feeder," "squares" and other names) were regional appellations for the same boys' game played with varying rules in many parts of England from the early 1700s onward. Along with its relatives stool-ball and the cat games it crossed the ocean with English colonists, and eventually followed its own independent evolutionary path, at the same time that back in England what was now generally called "rounders" was developing separately.

Cat, One old cat

The game of "cat" (or "cat-ball") had many variations but usually there was a pitcher, a catcher, a batter and fielders, but there were no sides (and often no bases to run). Often, as in English tip-cat, there was no pitcher and the "cat" was not a ball but an oblong wooden object, roughly football-shaped, which could be flipped into the air by striking one end, or simply a short stick which could be placed over a hole or stone and similarly flipped up. In other variants the batter himself tossed the ball into the air with his free hand, as in fungo. A feature of some versions of cat that would later become a feature of baseball was that a batter would be out if he swung and missed three times.

Another game that was popular in early America was "one ol' cat", the name of which was possibly originally a contraction of one hole catapult. In one ol' cat, when a batter is put out, the catcher goes to bat, the pitcher catches, a fielder becomes the pitcher, and other fielders move up in rotation. One ol' cat was often played when there weren't enough players to choose up sides and play townball. Sometimes running to a base and back was involved. "Two ol' cat" was the same game as one ol' cat, except that there were two batters; a diagram preserved in the New York Public Library is labeled "Four Old Cat" and depicts a square field like a baseball diamond and four batters, one at each corner.

Bat and ball
There are numerous 18th and early 19th-century references in England and especially America to "bat and ball". Unfortunately, there is no knowledge and information about the game besides the name, nor whether it was an alternate term for baseball or something else such as trap-ball, cat or even cricket. It might merely be a generic phrase for any game played with bat and ball. However, in 1859, Alfred Elwyn recalled of his childhood in New Hampshire in the 1810s:

This "bat and ball," at least, appears very clearly to be a form of early baseball/roundball/townball.

Town ball, round ball, Massachusetts base ball

Baseball, as it was before the rise to dominance of its altered New York variant in the 1850s and 60s, was known variously as base ball, town ball, round ball, round town, goal ball, field-base, three-corner cat, the New England game, or Massachusetts baseball. Generally speaking, "round-ball" was the most usual name in New England, "base-ball" in New York, and "town-ball" in Pennsylvania and the South. A diagram posted in the baseball collection on the New York Public Library's Digital Gallery website identifies a game played, "Eight Boys with a ball & four bats playing [F]our Old Cat" This game was apparently played on a square of 40 feet on each side, but the diagram does not make clear the rules or how to play the game. The same sheet of paper shows a diagram of a square – 60 feet per side with the base side having in its middle the "Home Goal", "Catcher", and "Striker", and with the corners marked as "1st Goal", "2nd Goal", "3rd Goal", and "4th Goal" as you travel counter-clockwise around the square. The note accompanying this diagram says, "Thirty or more players (15 or more on each side) with a bat and ball playing Town Ball, some times called Round Ball, and subsequently the so-called Massachusetts game of Base Ball".

Early baseball or town-ball had many, many variants, as would be expected of an informal boys' game, and most differed in several particulars from the game which developed in New York in the 1840s. Besides usually (but not always) being played on a 'rectangle' rather than a 'diamond,' with the batter positioned between fourth and first base (there were also variants with three and five bases), it was played by various numbers of players from six to over thirty a side, in most but not all versions there was no foul territory and every batted ball was in play, innings were determined on the basis of either "all out/all out" as in cricket or "one out/all out", in many all out/all out versions there was an opportunity for the last batter to earn another inning by some prodigious feat of hitting, pitching was overhand (underhand pitching was mandatory in "New York" baseball until the 1880s), and, perhaps most significantly, a baserunner was put out by "soaking" or hitting him with a thrown ball, just as in French poison-ball and Gutsmuth's .

As mentioned above, in 1829 The Boy's Own Book was reprinted in Boston, including the rules of rounders, and Robin Carver's 1834 The Book of Sports copied the same rules almost verbatim but changed "Rounders" to "Base or Goal ball" because, as the preface states, those "are the names generally adopted in this country" – which also implies that the game was "generally" known and played. In 1833 the Olympic Ball Club of Philadelphia was organized, and by 1837 the Gotham Base Ball Club would be formed in Manhattan, which would later split to form the Knickerbocker Club.

1835 saw the publication of Boy's Book of Sports which, confusingly, has chapters for both "Base ball" and "Base, or Goal-ball", which seem to be little if at all different; both were "all out, all out" townball with soaking and a three-strike rule. Of more interest is the fact that here appears the earliest use of the terms "innings" and "diamond".

The early 1840s saw the formation of at least three more clubs in Manhattan, the New York, the Eagle and the Magnolia; another in Philadelphia, the Athletic; and even a club in Cincinnati. By 1851 the game of baseball was well-established enough that a newspaper report of a game played by a group of teamsters on Christmas Day referred to the game as "a good old-fashioned game of base ball", and the 1858 report of the National Association of Base Ball Players declared that "The game of base-ball has long been a favorite and popular recreation in this country, but it is only within the last fifteen years that any attempt has been made to systematize and regulate the game."

The older game was recognized as being very different in character from the new "Knickerbocker" style. The New York Clipper of October 10, 1857, reported on a match between the Liberty Club of New Jersey and "a party of Old Fogies who were in the habit of playing the old fashioned base ball, which as nearly everyone knows, is entirely different from the base ball as now played." In 1860, the Olympic Ball Club of Philadelphia voted to change over to the "New York game", several traditionalist members resigned in protest. That same year the rival Athletic Club traveled to Mauch Chunk, Pennsylvania for a challenge match in which they competed against the local club in both town ball (the home team prevailed 45–43), and "New York" baseball (Athletic won easily, 34–2).

Round-ball persisted in New England longer than in other regions and during the period of overlap was sometimes distinguished as the "New England game" or "Massachusetts baseball"; in 1858 a set of rules was drawn up by the Massachusetts Association of Base Ball Players at the Phoenix Hotel in Dedham. This game was played by teams of ten to fourteen players with four bases 60 feet apart and no foul territory. The ball was considerably smaller and lighter than a modern baseball, and runners were still put out by "soaking".

Abner Doubleday myth

The myth that Abner Doubleday invented baseball in 1839 was once widely promoted and widely believed. There is no evidence for this claim except for the testimony of one unreliable man decades later, and there is persuasive counter-evidence. Doubleday himself never made such a claim; he left many letters and papers, but they contain no description of baseball or any suggestion that he considered himself prominent in the game's history. His New York Times obituary makes no mention of baseball, nor does a 1911 Encyclopædia article about Doubleday. The story was attacked by baseball writers almost as soon as it came out, but it had the weight of Major League Baseball and the Spalding publishing empire behind it. Contrary to popular belief, Doubleday was never inducted into the Baseball Hall of Fame, although a large oil portrait of him was on display at the Hall of Fame building for many years.

Doubleday's invention of baseball was the finding of a panel appointed by Albert Spalding, a former star pitcher and club executive, who had become the leading American sporting goods entrepreneur and sports publisher. Debate on baseball's origins had raged for decades, heating up in the first years of the 20th century, due in part to a 1903 essay baseball historian Henry Chadwick wrote in Spalding's Official Baseball Guide stating that baseball gradually evolved from English game of "rounders". To end argument, speculation, and innuendo, Spalding organized the Mills Commission in 1905. The members were baseball figures, not historians: Spalding's friend Abraham G. Mills, a former National League president; two United States Senators, former NL president Morgan Bulkeley and former Washington club president Arthur Gorman; former NL president and lifelong secretary-treasurer Nick Young; two other star players turned sporting goods entrepreneurs (George Wright and Alfred Reach); and AAU president James E. Sullivan.

The final report, published on December 30, 1907, included three sections: a summary of the panel's findings written by Mills, a letter by John Montgomery Ward supporting the panel, and a dissenting opinion by Henry Chadwick. The research methods were, at best, dubious. Mills was a close friend of Doubleday, and upon Doubleday's death in 1893 Mills orchestrated his memorial service and burial. Doubleday had been a prominent member of the spiritualist Theosophical Society, in which Spalding's wife was deeply involved and in whose compound in San Diego Spalding was residing at the time. Wright and Reach were effectively Spalding's employees, as he had secretly bought out their sporting-goods businesses some years before.  AAU president and Commission secretary Sullivan was Spalding's personal factotum. Several other members had personal reasons to declare baseball as an "American" game, such as Spalding's strong American imperialist views. The Commission found an appealing story: baseball was invented in a quaint rural town without foreigners or industry, by a young man who later graduated from West Point and served heroically in the Mexican–American War, Civil War, and U.S. wars against Indians.

The Mills Commission concluded that Doubleday had invented baseball in Cooperstown, New York in 1839; that Doubleday had invented the word "baseball", designed the diamond, indicated fielders' positions, and written the rules. No written records in the decade between 1839 and 1849 have ever been found to corroborate these claims, nor could Doubleday be interviewed (he died in 1893). The principal source for the story was one letter from elderly Abner Graves, who was a five-year-old resident of Cooperstown in 1839. Graves never mentioned a diamond, positions or the writing of rules. What's more, his reliability as a witness was challenged because he spent his final days in an asylum for the criminally insane.  Doubleday was not in Cooperstown in 1839 and may never have visited the town. He was enrolled at West Point at the time, and there is no record of any leave time. Mills, a lifelong friend of Doubleday, never heard him mention baseball, nor is there any mention of the game in Doubleday's autobiography. In character, Doubleday was bookish and sedentary, with no observable interest in athletics of any sort.

Versions of baseball rules and descriptions of similar games have been found in publications that significantly predate his alleged invention in 1839. Despite this, the ballpark built in 1939 only a few blocks down from the Hall of Fame still bears the name "Doubleday Field". However, aside from the artificial intrusion of the person of Doubleday and the village of Cooperstown, the Mills report was not entirely incorrect in its broad outline: a game related to English rounders was played in America from early times; it was supplanted by a variant form which originated in New York circa 1840. But this development happened in urban New York City, not pastoral Cooperstown, and the men involved were neither farm boys nor West Point cadets.

Knickerbocker rules

The earliest known published rules of baseball in the United States were written in 1845 for a New York City "base ball" club called the Knickerbockers. The purported organizer of the club, Alexander Cartwright, is one person commonly known as "the father of baseball". The rules themselves were written by the two-man Committee on By-Laws, Vice-president William R. Wheaton and Secretary William H. Tucker. One important rule, the 13th, outlawed "soaking" or "plugging", putting a runner out by hitting him with a thrown ball, introducing instead the concept of the tag; this reflected the use of a farther-traveling and potentially injurious hard ball. Another significant rule, the 15th, specified three outs to an inning for the first time instead of "one out, all out" or "all out, all out."  The 10th rule prescribed foul lines and foul balls and the 18th forbade runners advancing on a foul, unlike the "Massachusetts game" in which all batted balls were in play. The Knickerbockers also enlarged the diamond well beyond that of town ball, possibly to modern size depending on how "paces" is interpreted.

Evolution from the so-called "Knickerbocker Rules" to the current rules is fairly well documented. The most significant differences were  that overhand pitching was illegal, strikes were only counted if the batter swung and missed, "wides" or balls were not counted at all, a batted ball caught on the first bounce was an out, and a game was played to 21 "aces" or runs rather than for a set number of innings.

It is noteworthy, however, that the Knickerbocker Rules did not cover a number of basic elements of the game. For example, there was no mention of positions or the number of players on a side, the pitching distance was unspecified, the direction of base-running was left open, and it was never stated, though implied, that an "ace" was scored by crossing home plate. In all likelihood, all of these matters except the first were considered so intrinsic to baseball by this time that they were assumed; the number of players on a side, however, remained a matter of debate among clubs until fixed at nine in 1857, the Knickerbockers arguing unsuccessfully for seven-man teams.

On June 3, 1953, Congress officially credited Cartwright with inventing the modern game of baseball.  He was already a member of the Baseball Hall of Fame, having been inducted in 1938 for various other contributions to baseball. However, the role of Cartwright himself in the game's invention has been disputed. According to Major League Baseball's official historian, John Thorn, "Cartwright's plaque in the Baseball Hall of Fame declares he set the bases 90 feet apart and established nine innings as a game and nine players as a team. He did none of these things, and every other word of substance on his plaque is false." His authorship may have been exaggerated in a modern attempt to identify a single inventor of the game, and heavily advanced by a relentless public-relations campaign by his grandson. The 1845 Rules themselves are signed by the "Committee on By-Laws", William R. Wheaton and William H. Tucker. There is evidence that these rules had been experimented with and used by New York ball clubs for some time; Cartwright, in his 1848 capacity as club secretary (and a bookseller), was merely the first to have them printed up.

 Further evidence of a more collective model of New York baseball's development, and doubts as to Cartwright's role as "inventor", came with the 2004 discovery of a newspaper interview with William R. Wheaton, a founding member of the Gotham Baseball Club in 1837 and first vice president of the Knickerbocker Club, and co-author of its rules, eight years later.

If Wheaton's account, given in 1887, was correct, then most of the innovations credited to Cartwright were, in fact, the work of the Gothams before the Knickerbockers were formed, including a set of written rules. John Thorn, MLB's official historian, argued in his book Baseball in the Garden of Eden that four members of the Knickerbockers, namely Wheaton, Louis F. Wadsworth, Daniel "Doc" Adams and William H. Tucker, have stronger claims than Cartwright as "inventors" of modern baseball.

Legend holds that Cartwright also introduced the game in most of the towns where he stopped on his trek west to California to find gold, a sort of Johnny Appleseed of baseball. This story, however, arose from forged entries in Cartwright's diary which were inserted after his death.

It is however certain that Cartwright, a New York bookseller who later caught gold fever, umpired a game in Hoboken, New Jersey on June 19, 1846.  The game ended, and the Knickerbockers' opponents (the New York nine) won, 23–1. This was long believed to be the first recorded U.S. baseball game between organized clubs. However, at least three earlier reported games have since been discovered: on October 10, 1845, a game was played between the New York Ball Club and an unnamed club from Brooklyn, at the Union Star Cricket Grounds in Brooklyn; the New Yorks lost 22 to 1. The game was reported in the New York Morning News and True Sun, making it the first ever published baseball result. The New Yorks and Brooklyns played two more games on October 21 and 24, with the first on the New Yorks' home diamond at Elysian Fields and the rematch at the Star Cricket Grounds again.

One point undisputed by historians is that the modern professional major leagues that began in the 1870s developed directly from the amateur urban clubs of the 1840s and 1850s, not from the pastures of small towns such as Cooperstown.

Elysian Fields

In 1845, the Knickerbocker Club began using Elysian Fields in Hoboken to play baseball, following the New York and Magnolia Ball Clubs which had begun playing there in 1843.

At a preliminary meeting [of the Knickerbockers], it was suggested that as it was apparent they would soon be driven from Murray Hill, some suitable place should be obtained in New Jersey, where their stay could be permanent; accordingly, a day or two afterwards, enough to make a game assembled at Barclay street ferry, crossed over, marched up the road, prospecting for ground on each side, until they reached the Elysian Fields, where they "settled."
On October 21, 1845, the New York Ball Club played the second of their three games against a Brooklyn team there, the series being the first known inter-club baseball games. In June 1846 the Knickerbockers played the "New York nine" (probably the same New York Ball Club) in the first baseball game played between clubs according to codified rules. A plaque and baseball diamond street pavings at 11th and Washington Streets commemorate the event. By the 1850s, several Manhattan-based members of the National Association of Base Ball Players were using the grounds as their home field.

In 1865 the grounds hosted a championship match between the Mutual Club of New York and the Atlantic Club of Brooklyn that was attended by an estimated 20,000 fans and captured in the Currier & Ives lithograph The American National Game of Base Ball.

With the construction of two significant baseball parks enclosed by fences in Brooklyn, enabling promoters there to charge admission to games; the prominence of Elysian Fields began to diminish. In 1868 the leading Manhattan club, Mutual, shifted its home games to the Union Grounds in Brooklyn. In 1880, the founders of the professional National League's New York club and the Metropolitan Club of the American Association finally succeeded in siting a ballpark in Manhattan at the former Polo Grounds on 110th Street.

After 1845
The Knickerbockers published their rulebook in 1848, including one significant change: the introduction of the force-out, but only at first base. In 1852, the Eagle Club published their rules, and two years later the Knickerbockers, Eagles and Gothams met and agreed to a uniform set of rules to govern all three clubs, at least in match play, which for the first time set the pitching distance (15 paces). A preliminary meeting in 1855 between seven other clubs, five from New York and one each from Brooklyn and New Jersey, represented the first effort to form an organized league, although it came to nothing. However, in 1857 sixteen clubs from New York and environs sent delegates to a convention that standardized the rules, essentially by agreeing to the unified Knickerbocker-Gotham-Eagle rules with certain revisions: rather than playing to a set number of runs, games would consist of nine innings, and force-outs could now occur at any base. The convention also defined the distance between the bases unambiguously as 90 feet, and specified nine-man teams. The following year, twenty-five clubs including one from New Jersey established an ongoing governing body with officers, constitution and by-laws, but the National Association of Base Ball Players is conventionally dated from the first meeting in 1857. It governed through 1870 but it scheduled and sanctioned no games.

In 1858, clubs from the association played a cross-town, all-star series pitting Brooklyn clubs against clubs from New York and Hoboken.  On July 20, 1858, an estimated crowd of about 4,000 spectators watched New York and Hoboken defeat Brooklyn by a score of 22–18. The New York team included players from the Union, Empire, Eagle, Knickerbocker and Gotham clubs. The Brooklyn team included players from the clubs Excelsior, Eckford, Atlantic and Putnam. This was the first baseball game played before a paying crowd, with tickets priced at ten cents; the surplus receipts after costs were donated to charity. In a return match held August 17, 1858, and played at the Fashion Course in the Corona neighborhood of Queens, a slightly smaller crowd cheered Brooklyn to a win over New York and Hoboken by a score of 29–8. New York won a third game in the series, also played at the Fashion Course, on September 10, 1858.

By 1862 some NABBP member clubs offered games to the general public in enclosed ballparks with admission fees.

During and after the American Civil War (1861–1865), the movements of soldiers and exchanges of prisoners helped spread the game. As of the December 1865 meeting, the year the war ended, there were isolated Association clubs in Fort Leavenworth, St. Louis, Louisville, and Chattanooga, Tennessee, along with about 90 member clubs north and east of Washington, D.C. The game that was spread, however, was overwhelmingly the Knickerbocker version to the detriment of the older forms; as one periodical stated in 1865,

All of these clubs were nominally amateur, although by the late 1860s the strongest clubs' best players were being paid under the table.  For the 1869 season the NABBP, in an effort to take the corrupting money out of the amateur game, permitted the formation of professional teams. This move, however, backfired, as the pro game exploded in popularity and amateur club baseball quickly died out.  By far the most successful of the new professional clubs, the Cincinnati Red Stockings, recruited nationally and effectively toured nationally, and no one beat them until June 1870. Their success led to the founding of the National Association of Professional Base Ball Players in 1871 and its successor, the National League of Professional Base Ball Clubs in 1876, the elder of baseball's two Major Leagues and the oldest professional sports league in the world.

Already in the 19th century, the "old game" was invoked for special exhibitions such as reunions and anniversariesand for making moral points. Today hundreds of clubs in the U.S. play "vintage base ball" according to the 1845, 1858, or later rules (up to about 1887), usually in vintage uniforms.  Some of them have supporting casts that recreate period dress and manner, especially those associated with living history museums.

The origins of baseball were summarized in a documentary produced by Major League Baseball in 2009 titled Base Ball Discovered.

See also
Palant
History of baseball

References

Notes

Bibliography

Further reading

External links
Block, David. Cleveland, OH: Society for American Baseball Research. 2001. (checked August 5, 2006).
English Base-Ball (1796) – intermediate modern translation of J.C.F. Guts Muths, Ball mit Freystaten
1796 diagrams – by J.C.F. Guts Muths for Ball mit Freystaten
1796 caption – intermediate modern translation

Chronology of early references to baseball and related games
Short video about town ball and some modern-day reenactors keeping history alive in Cooperstown, NY
Evolution of 19th Century Baseball Rules
Civil War Vets Help Popularize Game of Baseball
Welsh Baseball Union

Origins
History of Dedham, Massachusetts

Origins of baseball


අවලංගු වාදය යනු  වහල් වෙළෙඳාම නවතා දමා හා බටහිර යුරෝපය හා ඇමරිකානු රටවල් තුල වහලුන් නිදහස් කරන මෙන්වූ ව්‍යාපාරයකි.

අවලංගු වාදය


JŽ 341 (popularno zvana Marijana) bila je oznaka serije prve nabavljene električne lokomotive u tadašnjem ŽTP Zagreb.

Lokomotiva je ušla u uporabu 1. prosinca 1955. i to na riječkoj pruzi gdje je trebala biti osnovno vučno sredstvo. Izvorna oznaka bila joj je E41 001, a naknadnom renumeracijom dobila je oznaku 341 001. Tijekom 1956. planovi Generalne direkcije Jugoslavenskih željeznica predviđali su povećanje prometa na pruzi Zagreb – Rijeka. Na tada raspisanom natječaju izabrana je snažnija lokomotiva talijanske tvrtke Ansaldo, označena kao serija JŽ 362 (poslije HŽ 1061). Marijana je bila jedina lokomotiva u ovoj seriji, i nisu nabavljani novi primjerci. Iz uporabe je povučena krajem 1980-ih.

Tehnički podatci
Proizvođač: Alsthom, Francuska
Električni sustav: 3000 V DC
Osovinski raspored: Bo'Bo'
Trajna snaga: 1375 kW
Najveća brzina: 95 km/h
Duljina preko odbojnika: 16024 mm
Ukupna masa lokomotive: 80 t
Najveće osovinsko opterećenje: 20 t

Izvori

Električne lokomotive
Električne lokomotive Jugoslavenskih željeznica
Francuska željeznička vozila

JŽ serija 341


Guy Hatfield (Oxford, 23 de fevereiro de 1977) também conhecido por seu nome artístico Hyper, é um DJ, e produtor britânico.

Em atividade desde 1999, atuou em colaborações com a banda The Prodigy entre 2004 e 2007, tendo juntos participado de gravações em estúdio, e concertos ao vivo na Europa.

Entre suas faixas mais famosas, estão "We Control", e "Spoiler", que foram utilizadas em Need for Speed Most Wanted (2005), e Cyberpunk 2077 (2020), respectivamente.

Discografia

Álbuns de estúdio
 We Control (2006)
 Suicide Tuesday (2008)
 The Panic (2011)
 Lies (2013)
 Symphony of Lies (2014)
 Bully (2015)

Álbuns de remixes

 Y3K: Deep Progressive Breaks (2000)
 Y3K: Soundtrack to the Future (2000)
 Bedrock Breaks (2001)
 Bedrock Breaks - Fractured (2003)
 Wired (2004)
 Inthemix Is Six - Along with Bass Kleph (2006)
 Rewired (2007)

EPs

 Twisted Emotion (2006)
 Catnip (2007)
 Centre Attraction (2008)
 Machine (2012)
 Cyberpunk (2019)
 Control (2021)

Referências

Ligações externas

Nascidos em 1977
DJs do Reino Unido
Naturais de Oxford
Breakbeat

DJ Hyper


is a district located in Okinawa Prefecture, Japan.

As of 2003, the district has an estimated population of 169,332 and the density of 1,216.03 persons per km2. The total area is 139.25 km2.

Towns and villages
Chatan
Kadena
Nishihara
Kitanakagusuku
Nakagusuku
Yomitan

Mergers
On April 1, 2005 Katsuren and Yonashiro were merged with the old cities of Gushikawa and Ishikawa to form the new city of Uruma.

Districts in Okinawa Prefecture

Nakagami District, Okinawa


Adaklı (Eski adı: Azakpert), 1987 yılında, Bingöl iline bağlı bir ilçe statüsüne kavuşmuştur. Bu tarihten önce Kiğı ilçesine bağlı bir nahiye idi.

Tarihçe
Uzun süre Kiğı ilçesiyle birlikte Erzurum'a bağlı bir köy statüsünü sürdüren Adaklı, 1926 yılında Erzincan iline, 1936 yılında nahiye olarak Bingöl iline bağlanmıştır.

Kasabanın 1960'lı yıllara dek kullanılan eski adı Azaxpert, Ermenice Asdğapert (Աստղաբերդ) yani "Yıldız Kalesi" adından gelir. Bu isim, Ermenilerin Hıristiyanlık öncesi dönemde ibadet ettiği tanrıçalardan Asdğik ("Yıldız Hanım", Astarte, Venüs) ile alakalı olmalıdır; zira Hıristiyanlık öncesinde bu yörede önemli bir Asdğik tapınağı bulunduğu bilinmektedir.

Kasabayı oluşturan mahallelerden Döşlüce Mahallesinin eski adı olan Seğank (Սեղանք) Ermenice "sunaklar, altarlar" anlamına gelir ve olasılıkla Adaklı adına ilham kaynağı olmuştur. Seğank adı 4. yüzyıl sonuna ait olan Byzantion'lu Faustus Vekâyinamesinde ilk kez zikredilmiştir. Danatepe Mahallesinin eski adı olan Pulur (Բլուր) Ermenice "höyük" demektir.

Coğrafya
İlçenin köyleri ile birlikte yüzölçümü 879 km²'dir. Bu da, il yüzölçümünün yüzde 10.82'sine tekabül etmektedir. İlçe merkezinin deniz seviyesinden yüksekliği 1500 metredir. İl merkezinden uzaklığı 66 kilometredir.

İlçede ilçe belediyesi dışında belediye bulunmamaktadır. Belediye sınırları içindeki mahalle sayısı 5'tir. İlçenin 35 köyü ve bu köylere bağlı 75 mezrası bulunmaktadır.

Nüfus

Kaynakça

Dış bağlantılar
 Adaklı Kaymakamlığı

İlçe taslakları

Adaklı, Bingöl


An orange box is a piece of hardware or software that generates caller ID frequency-shift keying (FSK) signals to spoof caller ID information on the target's caller ID terminal.

See also
 Blue box

References

Caller ID
Phreaking boxes

Orange box


Phoenicopterus flamingo familyası Phoenicopteridae içinde yer alan bir kuş cinsidir.

Taksonomi
Phoenicopterus cinsi, İsveçli doğa bilimci Carl Linnaeus tarafından 1758 yılında yalnızca Karayip flamingosu (Phoenicopterus ruber) olarak tek bir tür ile Systema Naturae eserinin onuncu baskısında tanımlandı. Cins adı Latince "flamingo" anlamına gelen sözcüktür.

Türler
Cins içinde üç tür sınıflandırılır.

Kaynakça

Phoenicopterus
Carl Linnaeus tarafından adlandırılmış taksonlar
Kuş cinsleri

Phoenicopterus


Octavian Vintilă (n. 22 iunie 1938, Ploiești, județul Prahova) este un fost scrimer român specializat pe sabie, apoi un comentator sportiv.

Carieră
Din copilărie era pasionat de duelurile cu spade din lemn. S-a apucat de scrimă la CS Petrolul din Ploiești, sub îndrumarea lui Ion Popescu, apoi a lui Vasile Chelaru. La vârsta de 20 ani s-a alăturat clubului Steaua București, cu care a fost campion republican pe echipe toată cariera sa, cu excepția anului 1961. A cucerit și titlul național la individual în 1968 și în 1969. Cu lotul olimpic al României a participat la Jocurile Olimpice de vară din 1964 de la Tokyo și la cele din 1972 de la München, unde România s-a clasat pe locul 4 la proba pe echipe.

După ce s-a retras din activitate competițională, a devenit arbitru internațional de scrimă și a fost vicepreședinte Federației Române de Scrimă din 1975 până în 2000. În paralel, a devenit jurnalist, lucrând la biroul de presă al clubului Steaua împreună cu Cristian Țopescu. Apoi a fost comentator sportiv și realizator de programe la Radio România Actualități. De-a lungul carierei sale a comentat șase ediții ale Jocurilor Olimpice, începând cu ediția din 1976. A fost președintele Asociației Presei Sportive (APS) din România din 2006 până în 2011. Pentru realizările sale a fost ridicat la gradul de comandor în Ordinul Național "Serviciul Credincios".

Referințe

Legături externe

Scrimeri olimpici români
Sabreri
Scrimeri la Jocurile Olimpice de vară din 1964
Scrimeri la Jocurile Olimpice de vară din 1972
Comentatori sportivi români

Octavian Vintilă


Unter den Greifvögeln wird nach der Art, wie die Beute getötet wird, zwischen Grifftöter und Bisstöter unterschieden. Der Ausdruck ist in der Ornithologie nicht allgemein üblich, wird aber verbreitet in der Jägersprache und der Fachsprache der Falknerei verwendet.

Zuerst unterschied der Ornithologe, Jagdkundler und Falkner Heinz Brüll 1937 zwischen "Grifftötern mit Reißhaken-Schneideschnabel" und "Griffhaltern mit Reißhaken-Beißschnabel" Bei den Grifftötern ist die Klaue der ersten Zehe ("Fangklaue") und der zweiten Zehe ("Atzklaue") besonders lang und länger als diejenigen der dritten und vierten Zehe. Bei den Griffhaltern sind alle Klauen ungefähr gleich lang.

Im Unterschied zum Bisstöter (hierzu gehören im Allgemeinen alle Falkenartigen), der die Beute durch einen Nackenbiss tötet und die Krallen lediglich zum Festhalten der Beute nutzt, erlegt der Grifftöter seine Beute allein mit Hilfe seiner langen und äußerst kräftigen Krallen. Zu den Grifftötern gehören im Besonderen die Habichtartigen und die meisten Adler. Grifftöter sind häufig an ihren langen Beinen zu erkennen, die es ihnen ermöglicht, auch große, wehrhafte Beute zu erlegen, da diese durch die langen Beine auf Distanz gehalten werden kann.

Einzelnachweise

Ornithologie

Grifftöter


47162 Chicomendez este un asteroid din centura principală de asteroizi.

Descriere
47162 Chicomendez este un asteroid din centura principală de asteroizi. A fost descoperit pe  la Monte Agliale de Matteo Santangelo. Asteroidul prezintă o orbită caracterizată de o semiaxă mare de 2,23 ua, o excentricitate de 0,10 și o înclinație de 6,5° în raport cu ecliptica.

Vezi și
 Lista planetelor minore: 47001-48000
 Centura de asteroizi

Referințe

Obiecte astronomice descoperite în 1999
Centura de asteroizi

47162 Chicomendez


Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occurs due to deficiency of the red blood cell surface protein DAF, which normally inhibits such immune reactions. Since the complement cascade attacks the red blood cells within the blood vessels of the circulatory system, the red blood cell destruction (hemolysis) is considered an intravascular hemolytic anemia. Other key features of the disease, such as the high incidence of venous blood clot formation, are incompletely understood.

PNH is the only hemolytic anemia caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol or GPI) leading to the absence of protective exterior surface proteins that normally attach via a GPI anchor. It may develop on its own ("primary PNH") or in the context of other bone marrow disorders such as aplastic anemia ("secondary PNH"). Only a minority of affected people  have the telltale red urine in the morning that originally gave the condition its name.

Allogeneic bone marrow transplantation is the only cure, but has significant rates of additional medical problems and death. The monoclonal antibody eculizumab reduces the need for blood transfusions and improves quality of life for those affected by PNH. Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to the extent that it may be equivalent to that of the general population. Eculizumab costs at least US$440,000 for a single year of treatment and has been reported as one of the world's most expensive drugs.

Signs and symptoms
The classic sign of PNH is red discoloration of the urine due to the presence of hemoglobin  and hemosiderin from the breakdown of red blood cells. As the urine is more concentrated in the morning, this is when the color is most pronounced. This phenomenon mainly occurs in those who have the primary form of PNH, who will notice this at some point in their disease course. The remainder mainly experience the symptoms of anemia, such as fatigue, shortness of breath, and palpitations.

A small proportion of patients report attacks of abdominal pain, difficulty swallowing and pain during swallowing, as well as erectile dysfunction in men; this occurs mainly when the breakdown of red blood cells is rapid, and is attributable to spasm of smooth muscle due to depletion of nitric oxide by red cell breakdown products.

Forty percent of people with PNH develop thrombosis (a blood clot) at some point in their illness. This is the main cause of severe complications and death in PNH. These may develop in common sites (deep vein thrombosis of the leg and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in those with PNH.

Pathophysiology

All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding environment. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid-protein structures on the surface of blood cells.

The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. The gene that codes for PIGA is located on the X chromosome. As males have only a single X chromosome and, in females, one is silenced through X-inactivation), only one active copy of the gene for PIGA is present in each cell regardless of sex. A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane. When this mutation occurs in a hematopoietic stem cell in the bone marrow, all of the cells it produces will also have the defect.

Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins. Although red blood cells, white blood cells, and platelets are targeted by complement, red blood cells are particularly vulnerable to lysis. The complement system is part of the innate immune system and has a variety of functions, from destroying invading microorganisms by opsonization to direct destabilization by the membrane attack complex. The main proteins that protect blood cells from destruction are decay-accelerating factor (DAF/CD55), which disrupts formation of C3-convertase, and protectin (CD59/MIRL/MAC-IP), which binds the membrane attack complex and prevents C9 from binding to the cell.

The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.

Historically, the role of sleep and night in this disease (the "nocturnal" component of the name) has been attributed to acidification of the blood at night due to relative hypoventilation and accumulation of carbon dioxide in the blood during sleep. This hypothesis has been questioned by researchers who note that not all those with PNH have increased hemolysis during sleep, so it is uncertain how important a role sleep actually plays in this disease.

Diagnosis
Blood tests in PNH show changes consistent with intravascular hemolytic anemia: low hemoglobin, raised lactate dehydrogenase, raised bilirubin (a breakdown product of hemoglobin), and decreased levels of haptoglobin; there can be raised reticulocytes (immature red cells released by the bone marrow to replace the destroyed cells) if there is no concurrent problem with production of red cells (such as iron deficiency). The direct antiglobulin test (DAT, or direct Coombs' test) is negative, as the hemolysis of PNH is not caused by antibodies. If the PNH occurs in the setting of known (or suspected) aplastic anemia, abnormal white blood cell counts and decreased platelet counts may be seen at this. In this case, anemia may be caused by insufficient red blood cell production in addition to the hemolysis.

Historically, the sucrose lysis test, in which a patient's red blood cells are placed in low-ionic-strength solution and observed for hemolysis, was used for screening.  If this was positive, the Ham's acid hemolysis test (after Dr Thomas Ham, who described the test in 1937) was performed for confirmation. The Ham test involves placing red blood cells in mild acid; a positive result (increased RBC fragility) indicates PNH or Congenital dyserythropoietic anemia. This is now an obsolete test for diagnosing PNH due to its low sensitivity and specificity.

Today, the gold standard is flow cytometry for CD55 and CD59 on white and red blood cells.  Based on the levels of these cell proteins, erythrocytes may be classified as type I, II, or III PNH cells. Type I cells have normal levels of CD55 and CD59; type II have reduced levels; and type III have absent levels. The fluorescein-labeled proaerolysin (FLAER) test is being used more frequently to diagnose PNH.  FLAER binds selectively to the glycophosphatidylinositol anchor and is more accurate in demonstrating a deficit than simply for CD59 or CD55.

Classification
PNH is classified by the context under which it is diagnosed:
 Classic PNH. Evidence of PNH in the absence of another bone marrow disorder.
 PNH in the setting of another specified bone marrow disorder such as aplastic anemia and myelodysplastic syndrome (MDS).
 Subclinical PNH. PNH abnormalities on flow cytometry without signs of hemolysis.

Screening
There are several groups where screening for PNH should be undertaken. These include patients with unexplained thrombosis who
are young, have thrombosis in an unusual site (e.g. intra-abdominal veins, cerebral veins, dermal veins), have any evidence of hemolysis (e.g. a raised LDH), or have a low red blood cell, white blood cell, or platelet count. Those who have a diagnosis of aplastic anemia should be screened annually.

Treatment

Acute attacks
There is disagreement as to whether steroids (such as prednisolone) can decrease the severity of hemolytic crises. Transfusion therapy may be needed; in addition to correcting significant anemia, this suppresses the production of PNH cells by the bone marrow, and indirectly the severity of the hemolysis. Iron deficiency develops with time, due to losses in urine, and may have to be treated if present. Iron therapy can result in more hemolysis as more PNH cells are produced.

Long-term
PNH is a chronic condition. In patients with only a small clone and few problems, monitoring of the flow cytometry every six months gives information on the severity and risk of potential complications. Given the high risk of thrombosis in PNH, preventive treatment with warfarin decreases the risk of thrombosis in those with a large clone (50% of white blood cells type III).

Episodes of thrombosis are treated as they would in other patients, but, given that PNH is a persisting underlying cause, it is likely that treatment with warfarin or similar drugs needs to be continued long-term after an episode of thrombosis.

Eculizumab
In 2007, the drug eculizumab was approved for the treatment of PNH. Prior to eculizumab, the median life expectancy of an individual with PNH was approximately 10 years. Since that time, short and mid-term studies of patients on eculizumab demonstrate that the drug returns the patient to a normal life expectancy, improves quality of life, and decreases the need for blood transfusions.

Eculizumab is controversial due to its high cost, as it is among the most expensive pharmaceuticals in the world, with a price of US$440,000 per person per year. Eculizumab is a humanized monoclonal antibody that acts as a terminal complement inhibitor. The drug interferes with the formation of the membrane attack complex in erythrocytes by binding to C5, compensating for the loss of protective function that results from CD59 deficiency. This alleviates the primary source of intravascular hemolysis, but it does not reduce the opsonization of erythrocytes caused by CD55 deficiency, so patients who receive this medication often still experience mild to moderate hemolysis. The U.S. Food and Drug Administration (FDA) has issued a black-box warning as those who take the medication have a 1,000 to 2,000-fold greater risk of invasive meningococcal disease. People on eculizumab are strongly advised to receive meningococcal vaccination at least two weeks prior to starting therapy and to consider preventative antibiotics for the duration of treatment.

Pegcetacoplan
Pegcetacoplan was approved for medical use in the United States in May 2021.

Iptacopan
Iptacopan is being developed by Novartis as a possible treatment, though no large trials have taken place as of 2022.

Epidemiology
PNH is rare, with an annual rate of 1-2 cases per million. The prognosis without disease-modifying treatment is 10–20 years.  Many cases develop in people who have previously been diagnosed with myelodysplastic syndrome. The fact that PNH develops in MDS also explains why there appears to be a higher rate of leukemia in PNH, as MDS can sometimes transform into leukemia or aplastic anemia.

25% of female cases of PNH are discovered during pregnancy. This group has a high rate of thrombosis, and the risk of death of both mother and child are significantly increased (20% and 8% respectively).

History
The first description of paroxysmal hemoglobinuria was by the German physician Paul Strübing (Greifswald, 1852–1915) during a lecture in 1881, later published in 1882. Later comprehensive descriptions were made by Ettore Marchiafava and Alessio Nazari in 1911, with further elaborations by Marchiafava in 1928 and Ferdinando Micheli in 1931.

The Dutch physician Enneking coined the term "paroxysmal nocturnal hemoglobinuria" (or haemoglobinuria paroxysmalis nocturna in Latin) in 1928, which has since become the default description.

References

External links

Rare diseases
Vascular-related cutaneous conditions
Acquired hemolytic anemia

Paroxysmal nocturnal hemoglobinuria


Die Abtei Notre-Dame in Laon wurde um 660 von der heiligen Salaberga gegründet. Ab dem 12. Jahrhundert wurde die Abtei Saint-Jean genannt, ohne dass ein formeller Wechsel des Patroziniums vorgenommen wurde.

Geschichte
Nach der Vita Sadalbergae hatte die austrische Adlige Salaberga nach zwei Ehen als Witwe in der Nähe von Langres ein Kloster gegründet, das sie aber nach drei Jahren, wohl in der zweiten Hälfte der 650er Jahre, aufgrund der politischen Wirrnisse der Zeit wieder aufgeben musste. Sie wandte sich nach Laon, wobei die Gründe für die Wahl Laons nicht bekannt sind, lag die Stadt doch nicht in Salabergas austrischer Heimat, sondern in Neustrien. Bischof Attola von Laon wies ihr ein freies Gelände im Südwesten der befestigten Stadt zu, westlich und südlich des alten römischen Cardo und Decumanus und in der Nähe der Stadtmauer, westlich der heute noch existierenden Porte d'Ardon. Hier gründete Salaberga ihr neues Kloster als Doppelkloster, das sie und ihre Familie selbst finanziell ausstatteten und auch bewohnten: Salabergas Bruder Leudin Bodon trat mit seiner Ehefrau Odile in das Kloster ein, bevor er 664 zum Bischof von Toul berufen wurde. Salabergas Vater lebte und starb im Kloster, gut sechs Wochen, nachdem Salaberga selbst 656 verstorben war. Salabergas Ehemann starb als hier als Archidiakon im Jahr 685, ebenso ihr Sohn Baudoin, der ebenfalls Archidiakon war. Ihre 20-jährige Tochter Anstrude wurde ihre Nachfolgerin.

Die Anfänge der Abtei standen unter der Aufsicht von Waldebert, dem dritten Abt des Klosters Luxeuil und damit unter der strengen Columbanregel, allerdings in der Fassung für Frauenklöster, die vermutlich er selbst Jahre zuvor gemeinsam mit Chagnoald, Attoals Vorgänger im Amt in Laon, für die Abtei Faremoutiers geschrieben hatte.

Aufgrund der Herkunft von Salabergas Familie und der Treue, die sie ihrer Heimat gegenüber hielten, wurde das Kloster ein Brückenkopf Austriens in Neustrien. Mit dem Sieg des austrischen Hausmeiers Pippin über die neustrische Konkurrenz wurde Notre-Dame de Laon eine Abtei, die nicht mehr dem Bischof von Laon unterstand.

Zu Beginn des 8. Jahrhunderts lebte vermutlich auch in der Abtei Notre-Dame jene Schreiberin Dulcia, deren als "Liber rotarum" (Livre des roues, Buch der Räder) bekannte Abschrift des De natura rerum Isidor von Sevillas das älteste Manuskript ist, das in Laon das Mittelalter überstanden hat.

Im 9. Jahrhundert war Notre-Dame de Laon dann zum einen zu einer Abtei geworden, die zusammen mit der benachbarten Königspfalz eine "Klosterpfalz" bildete, aber zum anderen auch zu einer Abtei, die der Versorgung von königlichen Töchtern und Witwen diente:
 Hildegard († wohl 860), die Tochter Ludwigs des Frommen war Äbtissin ein Abtei Notre-Dame, vermutlich Notre-Dame de Laon.
 Eadgifu, Tochter von Eduard der Ältere, König von Wessex, war als Witwe von Karl dem Einfältigen († 929) Äbtissin von Notre-Dame, bis sich im Jahr 951 Heribert den Alten, Graf von Meaux etc. heiratete, den langjährigen Gegner ihres Sohnes Ludwig IV., der ihr umgehend die Abtei entzog und sie seiner Ehefrau Gerberga († 984) gab, der Tochter des ostfränkischen Königs Heinrich I.; nach dem Tod Ludwigs (954) wurde aus der Nutznießerin im Jahr 959 die Äbtissin von Notre-Dame de Laon.

Mit dem Ende der Karolingerherrschaft und dem Rückgang der Bedeutung der Pfalzen begann auch der Rückgang der Bedeutung der Abtei Notre-Dame. Beim Aufstand der Bürger Laons gegen ihren Bischof Gaudry im Jahr 1112 wurde die Abtei teilweise niedergebrannt, allerdings in der Folgezeit auch weitgehend wieder aufgebaut, nachdem der Bischof das Kloster den Benediktinern anvertraut hatte. Aber auch trotz der Zerstörungen durch den Aufstand blieb Notre-Dame de Laon die älteste, reichste und angesehenste Abtei des Bistums. In dieser Zeit begann man aber auch, die Abtei nicht nach ihrer Hauptkirche Notre-Dame, sondern nach der zentraler gelegenen Kirche Saint-Jean zu nennen.

Die Abtei wurde zum Teil während der Hugenottenkriege zerstört, im 17. Jahrhundert neu gebaut, 1644 den Maurinern übergeben, ab 1742 erneut renoviert und 1781 schließlich zu einem städtischen Stift. Während der Revolution wurde das Kloster aufgelöst. Im Jahr 1800 wählte der Präfekt des Départments Aisne die aufgegebene Abtei zu seinem Sitz. Heute befindet sich am Standort der Abtei die gesamte Präfektur des Départements. Vom ehemaligen Kloster sind einige Strebepfeiler in der Stadtmauer, Teile eines Kirchenportals und der Kreuzgang aus dem 18. Jahrhundert erhalten. An die Abtei und deren Kreuzgang erinnert der Straßenname "Rue du Cloître Saint-Jean".

Architektur
Auf dem Gelände der Abtei wurden bereits in der Gründungsphase sieben Kirchen oder Kapellen errichtet:
  Die Hauptkirche war Notre-Dame, die, um sie von der Kathedrale Notre-Dame zu unterscheiden, auch Notre-Dame la Profonde genannt wurde. Diese Kirche stand am Südrand der Abtei unmittelbar an der Stadtmauer und dem dahinter steil abfallenden Gelände, daher der Name. Beim Volksaufstand von 1112 wurde Notre-Dame niedergebrannt, aber kurz danach im Stil der Gotik wiederaufgebaut. Diese Kirche wurde während der Belagerung Laons durch Heinrich IV. im Jahr 1594 von der Heiligen Liga teilweise zerstört, um die königlichen Truppen am Zugang zur Stadt zu hindern. Von der Kirche sind einige der Strebepfeiler der Klosterkirche Notre-Dame in der Stadtmauer (Rampe d'Ardon an der Porte d'Ardon, der früheren Porte royale) erhalten.
 Die zweite wichtige Kirche der Abtei war Saint-Jean, die im nördlichen Teil Klostergeländes und im Gegensatz zu Notre-Dame in der traditionellen West-Ost-Richtung stand. Auch Saint-Jean wurde 1112 niedergebrannt, aber erst Ende des 13. Jahrhunderts wiederaufgebaut. Von ihr sind Teile des Hauptportals erhalten, allerdings nicht an ihrem ursprünglichen Standort, sondern im Privatgarten des Präfekten. Der Rest der Kirche wurde während der Revolution zerstört. Die Kirche Saint-Jean war eigentlich den Propheten und Patriarchen geweiht, von denen Johannes der Täufer einer war. Ihre Lage und Bedeutung hat dazu geführt, dass ab dem 12. Jahrhundert das gesamte Kloster Saint-Jean de la Cité genannt wurde. Am Standort der Kirche Saint-Jean befindet sich heute das Verwaltungsgebäude der Präfektur.
 Rechts neben dem Chor von Saint-Jean stand die dritte Kirche, die allgemein den Aposteln gewidmet war, aber nur Saint-Pierre genannt wurde. Auch diese Kirche wurde 1112 niedergebrannt, aber ebenfalls kurz danach wieder aufgebaut. Diese Kirche war bereits bei der Gründung der Abtei für die Mönche des Klosters reserviert.
 Die vierte Kirche, Sainte-Croix, stand am Eingang der Abtei, angeblich, um Dämonen am Zugang zur Abtei zu hindern. Sie und der Zugang zur Abtei befanden sich im Osten des Geländes an der Porte royale und neben dem Eingang zur Königspfalz.
 Die fünfte Kirche war den Engeln gewidmet und wurde Saint-Michel genannt. Sie stand an der nördlichen Mauer des Klostergeländes.
 Die sechste Kirche war Saint Aspre gewidmet, Bischof von Toul; sie wurde im 12. Jahrhundert aufgegeben und in eine Kelter umgewandelt. An ihrem Standort befindet sich heute der Saal des Generalrats.
 Die siebte Kirche, die Maria Magdalena gewidmet war, war lediglich ein Oratorium links neben dem Haupteingang von Saint-Jean. Sie wurde 1341 auf Saint Flochel umgeweiht.

Literatur
 Bruno Krusch (Hrsg.): Vita Sadalbergae abbatissae Laudunensis. MGH SS rer. Merow. 5 (1910). S. 40–66.
 Suzanne Martinet: L'abbaye Notre-Dame la Profonde et les deux premières abbesses. In: Mémoires de la Fédération des Sociétés d'histoire et d'archéologie de l'Aisne. Band XV, 1969, S. 62–71f (online) (PDF; 774 kB)
 Annie Renoux: Palais et monastères: la question des Klosterpfalzen en France. In: Hans Rudolf Sennhauser (Hrsg.): Pfalz – Kloster – Klosterpfalz St. Johann in Müstair. 2011, ISBN 978-3-7281-3339-7, S. 93. (Skizze zur Lage der Abtei im Laon des 11. Jahrhunderts)

Anmerkungen

Kloster (7. Jahrhundert)
Bauwerk in Laon
Kloster in Hauts-de-France
Organisation (Département Aisne)
Abtei
Monument historique seit 1911
Laon

Abtei Notre-Dame de Laon


Hinokitiol (β-thujaplicin) je prirodni monoterpen, odnosno derivat, te jedan od thujaplicina pronađen u drveću iz porodice čempresovki (Cupressaceae).

Zbog svog antivirusnog, antimikrobnog i protuupalnog djelovanja, Hinokitiol se koristi pri izradi sredstava za oralnu upotrebu, kao i proizvodima koji se koriste prilikom liječenja. Poznat kao ionofor cinka i željeza, Hinokitiol je odobren kao prehrambeni aditiv. Podrijetlo imena potječe od činjenice da je prvobitno izoliran u Tajvanskom Hinokiju, 1936. godine. Prisutnost Hinokitiola javlja se u japanskom čempresu (Japanese Hinoki), dok oko 0.04% mase čini kod smreka kanarskih otoka (Juniperus cedrus), četinjača iz porodice čempresa - japanska hiba (Thujopsis dolabrata) i kod golemih tuja (Thuja plicata). Korištenjem otapala i ultrazvuka hinokitiol može biti vrlo lako izdvojen iz cedrova drva.

Strukturno je povezan s tropolom koji sadrži manjak izopropanola. Organski spojevi tropolona poznati su kao kelatni agensi.

Antimikrobno djelovanje
Hinokitiol je karakteriziran širokim spektrom bioloških aktivnosti, od kojih su mnoge navedene i opisane u literaturi. Prvo i najznačajnije jest antimikrobno djelovanje koje omogućuje borbu organizma protiv bakterija i gljivica, neovisno o otpornosti na antibiotike.

Hinokitiol je pokazao pozitivno djelovanje na Streptococcus pneaumonie, Streptococcus mutans i Streptococcus aureus.Također, Hinokitiol sadrži inhibitorne učinke na klamidiju, odnosno Chlamydia trachomatis te može biti korišten lijek.

Antiviralno djelovanje
Novija istraživanja pokazala su kako Hinokitiol sadrži antivirusno djelovanje kada se koristi s cinkom u borbi protiv humanih virusa, uključujući Rinovirus, Koksaki virus i Mengovirus. Liječenje virusnih infekcija stvara velik ekonomski napredak i stvara velik značaj Svjetskoj zdravstvenoj organizaciji. Oštećujući virusni poliprotein, Hinokitiol inhibira replikaciju virusa, no ova mogućnost striktno ovisi o dostupnosti dvovalentnih iona metala jer Hinokitiol djeluje kao njihov kelator.

Prisutnost cinka u kombinaciji s Hinokitiolom podržava ove sposobnosti te daljni tekst govori više o tome.

Djelovanje
Uz širokospektralno antimikrobno djelovanje, Hinokitiol posjeduje i protuupalno te protuumorsko djelovanje, karakterizirano prilikom brojnih istraživanja in vitro stanica životinjskog podrijetla.

Hinokitiol inhibira ključne markere i upalne puteve, poput TNF-a i NF-kB-a te istražuje njihov potencijal pri liječenju kroničnih upala i autoimunih stanja. Istraživanja su pokazala da Hinokitiol pokazuje citotoksičnost na nekoliko istaknut čelija karcinoma pospješujući autofagične procese.

Istraživanja povezana s Koronavirusom
Potencijalna antiviralna svojstva Hinokitiola proizlaze prilikom njegovog djelovanja kao ionofor cinka. Hinokitiol omogućuje stapanje cinkovih iona sa stanicama koji potiču umnožavanje RNA virusa te na taj način inhibira replikaciju virusa.

Neki značajni RNA virusi sadrže virus ljudske gripe, poznat kao SARS. Ioni cinka bili su u stanju značajno inhibirati replikaciju virusa u samim stanicama, te su pokazali važnost dotoka cinka. Istraživanja su provedena uz korištenje cinkogov ionofora, čije je djelovanje vrlo slično Hinokitiolu.

Prilikom proučavanja stanica, zaključivo je da Hinokitiol inhibira razmnožavanje Rinovirusa, Koksaki virusa i Mengovirusa. Hinokitiol inhibira replikaciju Pikornavirusa ometajući aktivnosti virusnog poliproteina kako bi aktivnost Hinokitiola ovisila o dostupnosti iona cinka.

Ionofor željeza
Pokazalo se kako Hinokitiol obnavlja količinu hemoglobina kod glodavaca. Hinokitiol djeluje kao ionofor željeza te povezuje željezo u stanice, povećavajući razinu željeza.

Otprilike 70% željeza u ljudskom tijelu sadržano je unutar crvenih krvnih stranica, a posebno unutar proteina hemoglobina. Željezo je bitno za razvoj svih živih organizama, bilo ljudskih ili životinjskih, te djeluje kao ključni element nekolicine fizioloških funkcija. U važnije fiziološke funkcije ubrajamo transport kisika i sintezu deoksiribonukleinske kiseline (DNK). Transport elektrona i nedostatak željeza mogu dovesti do krvnih poremaćaja, odnosno anemije koja je vrlo opasna te može ima štetno djelovanje na fizičko i mentalno zdravlje.

Sinergično djelovanje cinka
Kao ionofor cinka, Hinokitiol sadrži sposobnost koja inhibira replikaciju virusa. Sažeto rečeno, Hinokitiol, kao ionofor cinka ima značajnu ulogu u transportu molekula stanica kroz plazmatsku ili intracelularnu membranu. Na taj se način povećava unutarćelijska koncentracija određenih atoma metala kao što je cink.

Zaključivo je da iskorištavanjem prednosti antivirusnih svojstva cinka u kombinaciji s Hinokitiolom pospješujemo brži unos cinka.

Istraživanja povezana s liječenjem karcinoma
Istraživanja sprovedena na životinjama pokazuju kako Hinokitiol inhibira metastazei sadrži proliferativni učinak na stanice raka.

Nedostatak cinka
Nedostatak cinka prikazan je u pojedinim stanicama raka, kao i vraćanje optimalne unutarstanične razine cinka koja potencijalno dovodi do supresije rasta tumora.

Hinokitiol jest cinkov ionofor, no još je uvijek potrebno provesti odgovarajuća istraživanja kako bi se utvrdile učinkovite koncentracije za medicinsku upotrebu.

 "Učinkovitost cinka u prehrani pri smanjenju rasta melanoma i eksperimentalnih metastaza"
 "Dijetalni nedostatak cinka pospješuje razvoj raka jednjaka"
 "Metaanaliza istraživanja: povezanost između razine cinka u serumu i raka pluća
 "Napredna istraživanja odnosa nedostatka cinka i srodnih mikro-RNA karcinoma jednjaka

Proizvodi koji sadrže Hinokitiol
Hinokitiol ima široku upotrebu pri izradi kozmetičkih proizvoda, pasta za zube, oralnih sprejeva, krema za sunčanje i u proizvodima koji potiču rast kose. Jedna od vodećih tvrtki koja prodaje proizvode na bazi Hinokitiola jest Hinoki Clinical.

Tvrtka je osnovana 1956. godine, nakon što je 1955. godine započelo prvo 'industijsko ekstrahiranje Hinokitiola'. Hinoki trenutno ima preko 18 različitih asortimana proizvoda, temeljenih na Hinokitiolu. Brand pod nazivom Relief Life pohvalio se s milijunskom prodajom svoje zubne paste pod nazivom Dental Series.

Ostali značajni proizvođači proizvoda na bazi Hinokitiola su Otsuka Pharmaceuticals, Kobayashi Pharmaceuticals, Taisho Pharmaceuticals i SS Pharmaceuticals. Osim područja Azije, i druge su tvrtke na području SAD-a i Australije, poput Swanson Vitamins® počele primjenjivati Hinokitiol. 2006. godine Hinokitiol je kategoriziran na listi domaćih tvari (Domestic Substances List) u Kanadi, kao ne-toksičan i ne-bioakumulativan za vodene organizme. Američka zajednica za zaštitu okoliša (EWG - Environmental Working Group) posvetila je stranicu Hinokitiolu, kao sastojku koji sadrži malu opasnost za izazivanje alergija, raka i toksičnosti gdje je zadovoljivo ocjenu 1-2. Usporedivši ocjenu i karakteristike Hinokitiola i propilparabena (Propylparaben), propilparaben pokazuje veliku opasnost i toksičnost. Europska komisija za poremećaje hormona procijenila je propilparaben endokrinim razaračem te dajući mu ocjenu 4-6 na istoj stranici EWG-a.

Dr ZinX
2. travnja 2020. godine, australijski proizvođač cinkovog oksida Advance Nanotek podnio je zahtjev s tvrtkom AstiVita Limited za izradu patenta antivirusnog sustava koji se sastoji od različitih proizvoda za oralnu njegu, čiji je glavni sastojak Hinokitiol.

Marka koja uključuje inovaciju proizvoda nazvan je Dr ZinX te za 2020. godinu predviđa predstavljanje svoje čuvene kombinacije cinka i Hinokitiola. 18. svibnja 2020. godine objavljeni su rezultati ispitivanja pod nazivom "Kvantitativni test za evaulaciju virucidnih aktivnosti na području medicine". Rezultati testa pokazali su '3.25 log', odnosno 99.9 postotnu redukciju čiste koncentracije u vremenskom razdoblju od pet minuta protiv tzv. mačjeg koronavirusa (Feline Coronavirus).

Cink se pokazao kao bitan dodatak prehrani, a istraživanja su pokazala kako 17,3% globalnog stanovništva sadrži neadekvatan unos.

Obećavajuća budućnost
Početkom 2000-ih, istraživači su prepoznali važnost Hinokitiola pri izradi lijekova, posebice onih koji se koriste za borbu protiv klamidije (Chlamydia trachomatis). Kemičar Martin Burke u suradnji je s kolegama sa Sveučilišta Illinois Urbana-Champaign i drugih institucija otkrio značajnu medicinsku upotrebu Hinokitiola. Cilj gospodina Burka bio je prevladati i normalizirati nepravilan transport željeza u životinjskim organizmima. Nedostatak nekoliko proteina može dovesti do manjka željeza u stanicama, odnosno do anemije, no čak može imati i suprotan učinak, tzv. hemokromatozu.

Koristeći kulture kvasca, osiromašenih genom surogata, istraživači su pregledali zbirku malih molekula koje upućuju na transport željeza i rast stanica. Hinokitiol se pokazao kao uspješan pri vraćanju funkcionalnosti stanica, te je daljnim napornim radom tima uspostavljen mehanizam kojim vraća ili smanjuje željezo. Istraživanja su vršena na sisavcima te je otkriveno da glodavci koji su služili za razmatranje nedostatka željeza, a naknadno su hranjeni su Hinokitiolom, stvaraju povrat unosa željeza u crijevima. Slična istraživanja, provedena na zebrama, pokazala su kako su molekule obnovile proizvodnju hemoglobina.Komentar na rad gospodina Burke-a, odnosno nadimak koji je dodijeljen djelovanju Hinokitiola jest "Molekula željeznog čovjeka". Nadimak je istovremeno pogodan, a i ironičan jer prevedeno ime nalaznika Nozoe-a na engleski jezik glasi "Čelični čovjek" (Iron Man). Značajna istraživanja također su provedena u oralnim aplikacijama Hinokitiola s obzirom na povećanu potražnju proizvoda koji se temelje na Hinokitiolu.

Jedno takvo istraživanje, pod naslovom "Antibakterijski učinak Hinokitiola protiv patogenih bakterija koje prevladavaju u oralnoj šupljini i gornjim dišnim putevima" povezano je s osam različitih institucija u Japanu, a daje zaključak da Hinokitiol pokazuje antibakterijsko djelovanje protiv širokog spektra patogenih bakterija, te sadrži nisku citotoksičnost prema ljudskim epitelnim stanicama.

Izvori

Organski spojevi

Hinokitiol


Galaktička ravnina (galaktički ekvator, galaktička ravnica, eng. galactic plane) je pojam iz astronomije. Predstavlja veliku kružnicu na nebeskoj sferi. Prolazi središnjom ravninom Kumove slame ili koje druge galaktike. Prema nebeskom ekvatoru nagnuta je za 63°.

Vidi
galaktički koordinatni sustav

Izvori

Galaktička astronomija

Galaktička ravnina


"Belly Full of Turkey" es el noveno episodio de la primera temporada de How I Met Your Mother. Se transmitió el 21 de noviembre de 2005.

Trama
Es hora del Día de Acción de Gracias, y Marshall y Lily van a visitar la familia de Marshall en Minnesota. Mientras que Marshall disfruta un juego inventado por su familia, Lily está en la cocina. Mientras ayuda allí, escucha qué tan grandes son los sobrinos de Marshall, y comienza a asustarse pensando que tendrá un bebé enorme. Finalmente, en la cena, Lily huye y se compra una prueba de embarazo. Luego, Marshall descubre que Lily ha sido arrestada por orinar en público, y se dirige a la estación para liberar a Lily y hablar con ella. Lily le dice a Marshall sus preocupaciones al criar una familia de "gigantes que aman la mayonesa en Minnesota", pero Marshall le asegura que no se quedarán en Minnesota, y alivia los miedos de Lily. Finalmente, Marshall y Lily descubren que no está embarazada, y regresan a Eriksen.

Mientras tanto, Robin y Ted no tienen planes para el día de Acción de Gracias, y deciden ayudar en un refugio. Cuando llegan, encuentran a Barney haciendo de voluntario, y piden para ayudar. El organizador les dice que ya tienen suficientes voluntarios, pero después de rogar un poco, pueden ayudar. Pronto después, descubren que no toda la comida que reciben es distribuida para los pobres; muchos voluntarios roban la comida, especialmente comida extraña. Ted, al ver que es egoísta, comienza a distribuir comida extraña a los necesitados. Ted, Robin y Barney son echados, y Barney (quién fue voluntario por un año) se enoja con Ted; al final parece que Barney hizo de voluntario para un servicio comunitario después de ser arrestado por orinar en público. Ted y Robin se ponen de acuerdo en ir a un club de strip, The Lusty Leopard, con Barney para el Día de Acción de Gracias, y Ted, en un acto de caridad, le paga a un extraño un baile en las piernas. Al ver esto, una bailadora de allí felicita a Ted por ese comportamiento, revelando su nombre: Tracy. En el año 2030, el Ted del futuro le cuenta a sus hijos, "Y esa es la historia de cómo conocí a su madre", sorprendiendo a los chicos antes que Ted revelase que estaba bromeando.

Música
 We Are Scientists - "Nobody Move, Nobody Get Hurt"
 The 88 - "You Belong to Me"
 Styx - Mr. Roboto
 Barney canta "Little Red Riding Hood" del álbum Into the Woods cuando hace de voluntario.

Referencias

Episodios de How I Met Your Mother

Belly Full of Turkey


An Vriesea unilateralis in uska species han Liliopsida nga syahan ginhulagway ni John Gilbert Baker, ngan ginhatag han pagkayana nga asya nga ngaran ni Carl Christian Mez. An Vriesea unilateralis in nahilalakip ha genus nga Vriesea, ngan familia nga Bromeliaceae. Waray hini subspecies nga nakalista.

Mga kasarigan

Vriesea

Vriesea unilateralis


Gulnæbbet turako () er en turakoart.

Gulnæbbet turako lever i Angola, Cameroun, Congo, DR Congo, Elfenbenskysten, Ækvatorialguinea, Gabon, Ghana, Guinea, Liberia, Nigeria og Sierra Leone. IUCN kategoriserer arten som ikke truet.

Noter
 Avibase - the world bird database

Eksterne henvisninger

Fugle fra Centralafrika
Fugle fra Vestafrika
Turakoer

Gulnæbbet turako


Birgit Laury var mit kunstnernavn er en dansk dokumentarfilm fra 2013 instrueret af Mikael Rasmussen efter eget manuskript.

Handling
Birgit Laursen har elsket musik lige siden hun var barn, og hun har altid drømt om at gøre karriere som sangerinde. Til trods for stor modstand og manglende støtte fra forældrene sneg hun sig til diverse sangkonkurrencer og endte med at tage springet og tage til Tyskland som 20-årig for at synge i et kendt tysk TV-orkester. I 1969 var hun med til at etablere bandet Love Generation, som fik stor succes i Tyskland. I filmen fortæller hun om sin opvækst, karriere og sine relationer til mænd og kærligheden, og hun opsøger gamle sangkollegaer og flammer i Tyskland.

Referencer

Eksterne henvisninger

Dokumentarfilm fra Danmark
Danske film fra 2013

Birgit Laury var mit kunstnernavn


Pharyngeal tuberkel er placeret på den nedre overflade af den basillære del af nakkebenet, cirka én cm anteriort til foramen magnum. På den hæfter den fibrøse raphe pharyngis på pharynx.

Det er hæftepunktet for musklen constrictor pharyngis superior.

Referencer

Hovedets anatomi

Pharyngeal tuberkel


Patronyme

 Flower Msuya (1959-), phycologue tanzanienne.
 Joyce Msuya (1968_), spécialiste du développement tanzanienne.

Msuya